Novel insight into a platelet-derived growth factor-C/Smad3 axis in liver fibrosis. Focus on "Role of Smad3 in platelet-derived growth factor-C-induced liver fibrosis".

LIVER FIBROSIS IS THE COMMON RESPONSE to chronic liver injury and is due to the abnormal accumulation of extracellular matrix (ECM). In response to injury, activated hepatic stellate cells (HSCs) proliferate and produce excess amounts of ECM in response to inflammatory cytokines and growth factors (1, 2, 7). Among these mediators, transforming growth factor(TGF) is the major profibrogenic cytokine, upregulating the expression of -smooth muscle actin ( -SMA) and type 1 collagen(COL1A) synthesis via Smad signaling pathway, while platelet-derived growth factor (PDGF) is a potent mitogen for HSCs via activation of extracellular signal-regulated protein kinase/mitogen-activated protein kinase and phosphoinositide-3-kinase pathways (2). Currently, inhibition of TGFand/or PDGF signaling pathways is considered as a promising antifibrotic strategy. The PDGF ligand family consists of four different types, named PDGF-A, -B, -C, and -D, respectively. During liver injury, PDGF ligands produced by activated HSCs, infiltrating macrophages, Kupffer cells, and biliary epithelial cells stimulate HSCs in an autocrine and paracrine manner (1, 2). Produced homoor heterodimerized PDGF ligands (PDGF-AA, -AB, -BB, -CC, and -DD) elicit their biological effects following binding to PDGFRand PDGFRtyrosine kinase receptors, which dimerize into either PDGFR, , or , depending on the type of PDGF dimers. Each PDGF-AA and -DD ligand specifically binds to PDGFRand PDGFR, respectively, whereas the PDGF-CC chain interacts with isomers of PDGFRand PDGFR. PDGF-BB can bind to all three receptors, which likely induces different effects of PDGF isomers on liver fibrosis (2). HSCs express both PDGFRand , but only PDGFRexpression is upregulated during HSC activation in vivo and in vitro (9), and accordingly, activation of PDGFRplays a major role in liver fibrosis. Thus, PDGFRbinding to PDGF ligands, such as PDGF-B and -D chains, have been speculated as important factors in liver fibrosis (2). However, PDGF-A or PDGF-C transgenic mice develop spontaneous liver fibrosis by upregulating TGF, whereas specific transgenic PDGF-B expression and PDGF-Dtreated HSCs accelerate activation of HSCs without increased levels of TGF, indicating a TGF-independent manner of activation (2, 3). In addition, TGF1 is reported to increase the mitotic effects of PDGF-BB by upregulating PDGFRexpression in HSCs (1). These findings are suggested to involve TGF/Smad signaling in the induction of PDGFRexpression at the transcriptional level. However, the reversal effect of PDGFR-mediated signaling that may regulate the TGF/Smad pathway remains unclear. In this issue of American Journal of Physiology-Cell Physiology, Lee et al. (5) provide convincing evidence supporting the significant role of PDGF-C in the progression of liver fibrosis. By using PDGF-C transgenic mice crossed with Smad3-deficient mice, the authors report that these mice show reduced liver fibrosis compared with PDGF-C transgenic mice. Decreased fibrosis is associated with decreased expression of -SMA, COL1A, and connective tissue growth factor (CTGF) without modification of PDGFRs and TGF1 in HSCs. These findings suggest that Smad3 signaling is associated in part with PDGF-C-mediated liver fibrosis and activation of HSCs. In addition, the authors demonstrate that Smad3-deficient HSC showed decreased proliferation in response to PDGF-CC treat-